Radiolabelled compounds which are subject to localization in particular organs or tumors therein are of great value for diagnosis of diseases of the human body. For example, thallium 201 and fatty acids labelled with carbon-11 and iodine-123 have been utilized as heart imaging agents. Also, various phosphorate ligands labelled with technetium-99m have been used to image infarcted regions of the heart. Although many useful radiolabelled compounds are known, there remains a need for the discovery of improved compounds which are effective for routine imaging of the brain. In particular, there remains a need for radiolabelled compounds which are useful in imaging dopamine D2 receptors in the brain.
A dopamine D2 ligand for single photon emission tomography (SPECT) imaging would ideally have great selectivity and high affinity for the D2 receptor, low nonspecific binding, and adequate brain uptake for imaging. The in vivo striatal:cerebellar ratios for [.sup.11 C]raclopride and [.sup.123 I]IBM have been reported as 4:1(1) and 2:1(2), respectively, in man. The striatum to cerebellar uptake ratio is representative of an agent's ability to differentiate areas of high and low dopamine D2 receptors occurring outside the striatum. These extrastriatal dopamine D2 receptors, in mesolimbic and mesocortical brain regions, have been postulated to be involved in the pathophysiology of schizophrenia and to be the site of action of neuroleptic drugs. While hypothesis remains controversial, studies of these receptors are difficult because radiolabelled dopamine D2 receptor ligands available by previous art are not adequate for studying limbic and cortical D2 receptors. The reasons for this are related to the comparatively low numbers of D2 receptors and the relatively high concentrations of other receptors, e.g., serotonergic and nonadrenergic in many of these regions.
Substituted benzamides such as sulpiride, raclopride, and IBZM are dopamine D2 specific ligands, but have only moderate affinity for the dopamine D2 receptor, rendering reliable in vivo and in vitro studies of extrastriatal D2 receptors using these ligands impossible. Other substituted benzamides of prior art such as eticlopride, emonapride (YM-09151-2) and spectramide have been reported to be selective and are very potent dopamine D2 ligands. However, while their receptor affinities may be adequate, [K.sub.D 90 pM, 57 pM, and 25 pM respectively], eticlopride and emonapride are very lipophilic(5). This results in moderate to high levels of nonspecific binding to lipids in the brain, which has a significant adverse effect on image contrast. Spectramide, which is structurally related to emonapride and therefore quite lipophilic, also shows relatively high nonspecific binding both in vitro and in vivo in rat brain.
Spiperone and its derivatives have very high affinity for the dopamine D2 receptor, but spiperone's high affinity for the serotonin type 2 receptor severely limits its use for studying cortical and limbic dopamine D2 receptors.